Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to investigate the relationship between the precruciate cortex (PreCtx) and the ventral lateral posterior nucleus (VPL) of the thalamus in the mechanisms of acupuncture analgesia. Neuronal responses in the nucleus VPL to electrical noxious stimulation of the superficial peroneal nerve were extracellularly recorded. Lidocaine was topically applied at PreCtx. Twenty minutes after the application electroacupuncture (EA) was employed at "Zusanli" and "Huantiao" points for 5 minutes. The nociceptive responses were recorded immediately after cessation of EA and consecutively recorded at the interval of 2 minutes. Similar procedures were made in the control group, in which 0.9% Nacl was topically applied at PreCtx. It was found that topical application of lidocaine at PreCtx did not influence the nociceptive responses of VPL neurons. Following topical application of lidocaine at PreCtx, the nociceptive responses were obviously inhibited 0', 4', 6', 10', and 12' after cessation of EA. In the saline control group the remarkable inhibitory effect of EA was observed 0'-8' after ceasing EA, The results showed that the inhibitory effect of EA in the test group was weaker than that in the control group. However, the difference was not statistically significant. It is suggested that PreCtx participates in the corticofugal modulation of EA effects in the nucleus VPL only to small extent.
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PMID:[Relationship between the precruciate cortex and the ventral lateral posterior nucleus of the thalamus in acupuncture analgesia]. 211 9

In anaesthetized cats, diencephalic regions were electrically stimulated while recording evoked responses from lumbar dorsal horn neurones and cardiovascular parameters. Neuronal responses to impulses evoked electrically in unmyelinated primary afferents were inhibited by stimulation in many diencephalic regions. Responses to non-noxious cutaneous stimulation (hair deflection) were inhibited at relatively few sites. Indirect circulatory measurements showed that this selective spinal inhibition was accompanied by increases in cardiac output and muscle blood flow but reduced cutaneous perfusion. This association between selective inhibition of nociceptive spinal neuronal responses and a cardiovascular response pattern associated with the defence reaction supports the proposal that analgesia could be an important component of defensive behaviour.
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PMID:Inhibition of spinal nociceptive transmission accompanies cardiovascular changes from stimulation in diencephalic 'defence' regions of cats. 376 34

Neuronal nicotinic acetylcholine receptors (NAChRs) are pentameric ligand-gated ion channel receptors which exist as different functional subunit combinations which apparently subserve different physiological functions as indicated by molecular biological and pharmacological techniques. It is possible to design and synthesize novel compounds that have greater selective affinities and efficacies than nicotine for different NAChRs, which should translate into different behavioral profiles and therapeutic potentials. Examples of NAChR agonists studied are nicotine, SIB-1508Y, SIB-1553A and epibatidine. These compounds have different degrees of selectivity for human recombinant NAChRs, different neurotransmitter release profiles in vitro and in vivo and differential behavioral profiles. Preclinical studies suggest that SIB-1508Y is a candidate for the treatment of the motor and cognitive deficits of Parkinson's disease, whereas SIB-1553A appears to have potential as a candidate for the treatment of Alzheimer's disease. Epibatidine has a strong analgesic profile, however the ratio between pharmacological activity and undesirable effects is so low that it is difficult to envisage the use of this compound therapeutically. Nicotine has a broad profile of pharmacological activity, for instance demonstrating activity in models for cognition and analgesia. As for epibatidine, the adverse effects of nicotine severely limits its therapeutic use in humans. The discovery of subtype-selective NAChR agonists such as SIB-1508Y and SIB-1553A provides a new class of neuropsychopharmacological agents with better therapeutic ratios than nonspecific agents such as nicotine.
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PMID:The potential of subtype-selective neuronal nicotinic acetylcholine receptor agonists as therapeutic agents. 958 43

Nicotinic acetylcholine receptors are members of the ligand-gated ion channel superfamily, that includes also gamma-amino-butiric-acid(A), glycine, and 5-hydroxytryptamine(3) receptors. Functional nicotinic acetylcholine receptors result from the association of five subunits each contributing to the pore lining. The major neuronal nicotinic acetylcholine receptors are heterologous pentamers of alpha4beta2 subunits (brain), or alpha3beta4 subunits (autonomic ganglia). Another class of neuronal receptors that are found both in the central and peripheral nervous system is the homomeric alpha7 receptor. The muscle receptor subtypes comprise of alphabetadeltagamma (embryonal) or alphabetadeltaepsilon (adult) subunits. Although nicotinic acetylcholine receptors are not directly involved in the hypnotic component of anesthesia, it is possible that modulation of central nicotinic transmission by volatile agents contributes to analgesia. The main effect of anesthetic agents on nicotinic acetylcholine receptors is inhibitory. Volatile anesthetics and ketamine are the most potent inhibitors both at alpha4beta2 and alpha3beta4 receptors with clinically relevant IC(50) values. Neuronal nicotinic acetylcholine receptors are more sensitive to anesthetics than their muscle counterparts, with the exception of the alpha7 receptor. Several intravenous anesthetics such as barbiturates, etomidate, and propofol exert also an inhibitory effect on the nicotinic acetylcholine receptors, but only at concentrations higher than those necessary for anesthesia. Usual clinical concentrations of curare cause competitive inhibition of muscle nicotinic acetylcholine receptors while higher concentrations may induce open channel blockade. Neuronal nAChRs like alpha4beta2 and alpha3beta4 are inhibited by atracurium, a curare derivative, but at low concentrations the alpha4beta2 receptor is activated. Inhibition of sympathetic transmission by clinically relevant concentrations of some anesthetic agents is probably one of the factors involved in arterial hypotension during anesthesia.
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PMID:The role of nicotinic acetylcholine receptors in the mechanisms of anesthesia. 1184 19

In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.
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PMID:Adenosine in the spinal cord and periphery: release and regulation of pain. 1278 73

Central nociceptive processing includes spinal and supraspinal neurons, but the supraspinal mechanisms mediating changes in pain threshold remain unclear. We investigated the role of forebrain neurons in capsaicin-induced hyperalgesia. Long-Evans rat pups at 21 days were randomized to undisturbed control group, or to receive tactile stimulation, saline injection (0.9% w/v) or capsaicin injection (0.01% w/v) applied to each paw at hourly intervals. Thermal paw withdrawal latency was measured 1 h later, forebrains were removed and purified forebrain neuronal membranes were assayed for adenylyl cyclase activity and opioid receptor function. Capsaicin-injected rats had decreased thermal latency (P < 0.0001) compared to the other groups. Neuronal membranes showed increased basal (P = 0.0003) and forskolin-stimulated (P=0.0002) adenylyl cyclase activity in the capsaicin group compared to other groups. The selective mu-opioid receptor agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO) was less effective in inhibiting adenylyl cyclase activity in the capsaicin group (P < 0.001) compared to other groups. These effects were naloxone-reversible and pertussis toxin-sensitive (P < 0.01) in the control, tactile stimulation and saline injection groups but not in the capsaicin group. Binding capacity and affinity for micro-opioid receptors were similar in all four groups, suggesting that receptor downregulation was not involved. Exposure to DAMGO increased [35S]GTPgammaS binding to neuronal membranes from the control, tactile and saline groups (P<0.001) in a naloxone-reversible and pertussis toxin-sensitive manner (P < 0.01) but not in the capsaicin group, suggesting mu-opioid receptor desensitization. Dose responses to systemic morphine were also reduced in the capsaicin group compared to the tactile group (P < 0.05). Capsaicin-induced hyperalgesia in 21-day-old rats was associated with an uncoupling of micro-opioid receptors in the forebrain. Opioid receptor desensitization in the forebrain may reduce opioidergic inputs to the descending inhibitory controls, associated with behavioral hyperalgesia and reduced responsiveness to morphine analgesia in capsaicin-injected young rats.
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PMID:Opioid receptor desensitization contributes to thermal hyperalgesia in infant rats. 1514 Jun 29

Neuronal nicotinic acetylcholine receptors comprise a heterogeneous class of cationic channels that is present throughout the nervous system. These channels are involved both in physiological functions (including cognition, reward, motor activity and analgesia) and in pathological conditions such as Alzheimer's disease, Parkinson's disease, some forms of epilepsy, depression, autism and schizophrenia. They are also the targets of tobacco-smoking effects and addiction. Neuronal nicotinic acetylcholine receptors are pentamers of homomeric or heteromeric combinations of alpha (alpha2-alpha10) and beta (beta2-beta4) subunits, which have different pharmacological and biophysical properties and locations in the brain. The lack of subtype-specific ligands and the fact that many neuronal cells express multiple subtypes initially hampered the identification of the different native nicotinic acetylcholine receptor subtypes, but the increasing knowledge of subtype composition and roles will be of considerable interest for the development of new and clinically useful nicotinic acetylcholine receptor ligands.
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PMID:Brain nicotinic acetylcholine receptors: native subtypes and their relevance. 1687 83

Advances in cannabis research have paralleled developments in opioid pharmacology whereby a psychoactive plant extract has elucidated novel endogenous signalling systems with therapeutic significance. Cannabinoids (CBs) are chemical compounds derived from cannabis. The major psychotropic CB delta-9-tetrahydrocannabinol (Delta(9)-THC) was isolated in 1964 and the first CB receptor (CB(1)R) was cloned in 1990. CB signalling occurs via G-protein-coupled receptors distributed throughout the body. Endocannabinoids are derivatives of arachidonic acid that function in diverse physiological systems. Neuronal CB(1)Rs modulate synaptic transmission and mediate psychoactivity. Immune-cell CB(2) receptors (CB(2)R) may down-regulate neuroinflammation and influence cyclooxygenase-dependent pathways. Animal models demonstrate that CBRs play a fundamental role in peripheral, spinal, and supraspinal nociception and that CBs are effective analgesics. Clinical trials of CBs in multiple sclerosis have suggested a benefit in neuropathic pain. However, human studies of CB-mediated analgesia have been limited by study size, heterogeneous patient populations, and subjective outcome measures. Furthermore, CBs have variable pharmacokinetics and can manifest psychotropism. They are currently licensed as antiemetics in chemotherapy and can be prescribed on a named-patient basis for neuropathic pain. Future selective peripheral CB(1)R and CB(2)R agonists will minimize central psychoactivity and may synergize opioid anti-nociception. This review discusses the basic science and clinical aspects of CB pharmacology with a focus on pain medicine.
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PMID:Therapeutic potential of cannabis in pain medicine. 1851 70

Aging is associated with the decline of cognitive properties. This situation is magnified when neurodegenerative processes associated with aging appear in human patients. Neuronal synaptic plasticity events underlie cognitive properties in the central nervous system. Caloric restriction (CR; either a decrease in food intake or an intermittent fasting diet) can extend life span and increase disease resistance. Recent studies have shown that CR can have profound effects on brain function and vulnerability to injury and disease. Moreover, CR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which modulate pain sensation, enhance cognitive function, and may increase the ability of the brain to resist aging. The beneficial effects of CR appear to be the result of a cellular stress response stimulating the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors, neurotransmitter receptors, protein chaperones, and mitochondrial biosynthesis regulators. In this review, we will present and discuss the effect of CR in synaptic processes underlying analgesia and cognitive improvement in healthy, sick, and aging animals. We will also discuss the possible role of mitochondrial biogenesis induced by CR in regulation of neuronal synaptic plasticity.
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PMID:Molecular bases of caloric restriction regulation of neuronal synaptic plasticity. 1875 9

Neuronal nicotinic acetylcholinic receptors (nAChR) are promising targets for the development of novel analgesics. Nicotine and other nAChR-agonists produce profound analgesia in rodent models of acute and persistent pain. However, significant side-effects are of concern. Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine. Little is known about its analgesic properties. In the present study, the S(-)- and R(+)-enantiomers of nornicotine were characterized with regard to analgesia and side-effects profile. Efficacy was demonstrated in rat models of pain where central sensitization is involved: i.e. the chronic constriction nerve injury model of peripheral neuropathy and the formalin model of tonic inflammatory pain. The desirable (analgesic) properties resided predominantly in the S(-)- rather than the R(+)-enantiomer. In contrast, undesirable effects (motor in-coordination, reduced locomotor activity, ataxia) were more pronounced with the R(+)-enantiomer. This is an interesting finding, which may suggest separation of toxicity from analgesia by utilization of S(-)-enantiomer of nornicotine. Maximum analgesic effectiveness without significant side-effects was achieved when S(-)-nornicotine (sub-analgesic dose) was combined with a low-dose of the micro-opioid, morphine. These preclinical data suggest that S(-)-nornicotine may be of value, either alone or in combination with an opioid, for treatment of a broad-spectrum of pain (i.e. nociceptive, neuropathic, and mixed pain).
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PMID:The analgesic and toxic effects of nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain. 1980 Sep 11


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